Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
  • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
  • C07D211/12—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
  • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
  • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

• the present invention concerns and has for its object the provision of compounds corresponding to formula I ##SPC2##
• X is hydrogen or hydroxy
• m is an integer from 0 to 2
• n is an integer from 0 to 7
• the sum (m+n) is from 1 to 7
• each of R 1 and R 2 is hydrogen, lower alkyl, lower alkoxy, halo or trifluoromethyl, or a therapeutically acceptable acid addition salt thereof, of corresponding pharmaceutical compositions and of methods for the preparation and application of these products, which are useful neuroleptic agents.
• the radical C n H 2n +-1 is either alkyl, alkenyl, cycloalkyl or cycloalkyl-alkyl of 1-7 carbon atoms, e.g. methyl, ethyl, n- or i-propyl or -butyl, straight or branched pentyl, hexyl or heptyl; allyl or methallyl; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; cyclopropyl-methyl, cyclobutyl-ethyl, cyclopentyl-methyl or cyclohexyl-methyl.
• alkyl radicals C n H 2n +1 wherein n is an integer from 1 to 4, especially methyl.
• radicals R 1 and R 2 both represent preferably hydrogen, but one or both are also lower alkyl e.g. that mentioned above; lower alkoxy, e.g. methoxy, ethoxy, n or i-propoxy or butoxy; halo, e.g. fluoro, chloro or bromo; or trifluoromethyl.
• lower alkoxy e.g. methoxy, ethoxy, n or i-propoxy or butoxy
• halo e.g. fluoro, chloro or bromo
• trifluoromethyl trifluoromethyl
• Salts of the compounds of formula 1 are preferably therapeutically acceptable acid addition salts derived, for example, from the inorganic or organic acids listed below.
• the compounds of the invention exhibit valuable pharmacological properties. Besides antihypertensive activity, they show especially neuroleptic effects. This can be demonstrated in animal tests, using advantageously mammals such as mice, rats, and especially monkeys, as test objects. Said compounds are applied either enterally or parentally, e.g. orally, subcutaneously, intraperitoneally or intravenously, for example, within gelatin capsules, suspended in cornstarch or in the form of aqueous solutions or suspensions respectively.
• the oral dosage may range between about 0.1 and 100 mg/kg/day, preferably between 0.5 and 50 mg/kg/day and advantageously between about 0.3 and 2.5 mg/kg/day.
• Said compounds produce, for example, at the above oral doses, especially between about 0.1 and 5 mg/kg/day, a decrease of the leverpressing avoidance responses of squirrel monkeys.
• the test procedure used is the following: Monkeys were trained to press a lever to avoid the onset of an electric foot shock. Each lever press postpones the shock for 20 -seconds. Whenever the monkey fails to press the lever once within a 20 -second period, brief (0.5 sec.) shocks are delivered at 20-second intervals until the animal again presses the lever. Under control conditions the monkeys press the lever at a moderately steady rate and seldom receive more than five or six shocks during a 4-hour experimental session.
• the compounds of the invention are useful neuroleptics, for example, in the treatment of management or aggression, agitation, and autism or anxiety in warm-blooded animals, preferably mammals. They are also valuable antihypertensives or intermediates for other preparations, preferably pharmacologically useful products.
• Preferred and highly active compounds of the invention are those of formula I, in which X is hydrogen or hydroxy m is the integer 0 or 1, n is such from 0 to 4, (m+n) is 1 to 4, and each of R 1 and R 2 is hydrogen, alkyl or alkoxy with up to 4 carbon atoms, fluorine, chlorine, bromine or trifluoromethyl, or a therapeutically acceptable acid addition salt thereof.
• Especially important neuroleptic agents are compounds of formula I, in which X is hydroxy, m is the integer 0, n is either 1 or 2, and each of R 1 and R 2 is hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine or trifluromethyl, or a therapeutically acceptable acid addition salt thereof.
• the most promising compound of the invention is the 4' -fluoro-4-[4-( ⁇ -hydroxy- ⁇ -methylbenzyl)-piperidino]-butyrophenone, especially its dextrorotatory optical isomer, or a therapeutically acceptable acid addition salt thereof, which exhibit outstanding effects in the above-described test system (Sidman procedure).
• the dextrorotatory methanesulfonate thereof when, administered once at dosages between 0.3 and 5 mg/kg to squirrel monkeys, displays a very rapid onset of action of unusual long duration without observable neurological deficit.
• the compounds of the invention are prepared according to known methods, for example, by:
• Y is a reactively esterified hydroxy group and m, n, X, R 1 and R 2 are as defined previously, or
• Z is a ketalized oxo or thiono group derived from a lower alkanediol or dithiol or a lower thioalkanol and, if desired, converting any resulting compound into another compound of the invention.
• a reactively esterified hydroxy group Y is preferably such derived from a strong mineral acid or an aliphatic or aromatic sulfonic acid, e.g. sulfuric, methane, ethane-, benzene-, toluene- or camphor sulfonic acid but preferably that of a hydrohalic acid, e.g. hydrobromic, hydriodic or especially hydrochloric acid.
• a strong mineral acid or an aliphatic or aromatic sulfonic acid e.g. sulfuric, methane, ethane-, benzene-, toluene- or camphor sulfonic acid
• a hydrohalic acid e.g. hydrobromic, hydriodic or especially hydrochloric acid.
• the corresponding condensation is preferably carried out in the presence of basic agents, for example, alkali or alkaline earth metal carbonates, hydroxides, or lower alkoxides, such as sodium, potassium or calcium carbonate, sodium or potassium hydroxide, methoxide or ethoxide.
• basic agents for example, alkali or alkaline earth metal carbonates, hydroxides, or lower alkoxides, such as sodium, potassium or calcium carbonate, sodium or potassium hydroxide, methoxide or ethoxide.
• organic nitrogen bases can be used, such as aliphatic or aromatic tertiary amines, for example tri-lower alkylamines, e.g. triethylamines; pyridine or collidine.
• a catalyst for example, an ion in common with the condensing agents, for example, where sodium carbonate is used, a crystal of sodium halide, preferably sodium iodide, is found to enhance the reaction.
• the hydrolyzing according to item (b) is carried out in the usual manner, for example in mixtures of organic and acidic aqueous mediums, especially alcoholic mineral or sulfonic acids e.g. those mentioned above.
• the compounds of the invention can be converted into each other by known methods.
• diluents preferably such as are inert to the reagent and being solvents thereof, of catalysts, condensing or reducing agents respectively and/or inert atmospheres, at low temperatures, room temperatue or elevated temperatures, at atmospheric or superatmospheric pressure.
• Solvents employed in the condensation reaction according to item (a) are preferably polar solvents, such as alcohols or ketones, for example, lower alkanols or simple or mixed lower alkanones, such as methanol, ethanol; acetone, 2-butanone or, above all, 4-methyl-2-pentanone. Also useful are polar aprotic solvents, such as lower alkanonic acid amides or di-lower alkylsulfoxides, e.g. dimethylformamide, dimethyeacetamide or dimethylsulfoxide.
• polar solvents such as alcohols or ketones, for example, lower alkanols or simple or mixed lower alkanones, such as methanol, ethanol; acetone, 2-butanone or, above all, 4-methyl-2-pentanone.
• polar aprotic solvents such as lower alkanonic acid amides or di-lower alkylsulfoxides, e.g. dimethylformamide, dimethyeace
• the compounds of the invention are obtained in the free form or in the form of their salts, depending on the conditions under which the process is carried out; the salts are also included in the present invention.
• Salts that are obtained can be converted into the free bases in known manner, for example, with alkalies or ion exchangers.
• Free bases that are obtained can be converted into salts by reaction with inorganic or organic acids, especially those that are suitable for the formation of therapeutically acceptable salts.
• Such acids are, for example, mineral acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric, nitric or perchloric acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g.
• salts of the invention for example, the picrates
• the bases can also be used for purification of the bases obtained; the bases are converted into salts, the salts are separated and the bases are liberated from the salts.
• a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.
• the invention further includes any variant of the present process, in which an intermediate product obtainable at any stage of the process is used as starting material and any remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts.
• those starting materials shouold be used in the process of the invention that lead to the formation of those compounds indicated above as being specially valuable.
• said piperidines are obtained by hydrogenation of the corresponding pyridines; it is preferably carried out catalytically in an inert solvent, or preferably in an aqueous acidic medium, such as aqueous acetic acid.
• the catalyst employed is preferably palladium on charcoal support.
• the pyridines in turn are prepared by the treatment of readily available 4-aroylpyridines with a corresponding aliphatic or cycloaliphatic metallic reagent and hydrolysis of the resulting adduct. This reaction involves preferably the addition of a lower alkyl magnesium halide to the carbonyl compound and hydrolysis of the reaction product with aqueous acidic reagents, to afford the pyridine-carbinols.
• 4-( ⁇ -hydroxyaralkyl)-piperidines contain substituents R 1 and R 2 sensitive to hydrogenation, they can be prepared by the addition of said metallic reagents to corresponding N-acyl-4-aroylpiperidines in the manner described above.
• the starting N-acyl-4-aroylpiperidines are prepared essentially as described in U.S. Pat. No. 3,576,810.
• the starting material used under item (b) is prepared as follows, employing similar reaction conditions as already described.
• a reactively converted 4'-fluoro-4-hydroxybutyrophenone is initially ketalized, e.g. treated with ethylene glycol or ⁇ -mercaptoethanol, in the presence of an acidic catalyst, to form the 1,3-dixolane or 1,3-oxathiolane thereof.
• This reaction is advantageously carried out in the presence of an inert solvent and one immiscible with water, in order to remove the water formed in the ketalization.
• the reaction is thus especially carried out at reflux temperatures in solvents such as aromatic hydrocarbons, for example, benzene, toluene or xylene.
• the water formed is removed by means of an azeotropic distillation trap.
• the acid catalyst employed is normally a sulfonic acid, for example, p-toluenesulfonic acid, but can also be a Lewis acid or a mineral acid, such as zinc chloride, boron trifluoride, hydrochloric or sulfuric acid.
• the resulting dioxolane or oxathiolane is then condensed in a similar manner described in the reaction under item (a) with a 4-aroylpiperidine, obtained as described in U.S. Pat. No. 3,576,810.
• the resulting condensation product is treated with a Grignard reagent, as described above, and hydrolyzed to form the starting material under item (b).
• Racemic products can likewise be resolved into the optical antipodes, for example, by separation of diastereomeric salts or esters thereof, e.g. by the fractional crystallization of d- or l- tartrates, -maleates, -malates -N-acetylphenylalaninates or -camphorsulfonates, and re-converting the diastereomeric salts or esters into the free antipodes, or using said ester intermediates direct in reaction (a).
• compounds of formula I are converted into their individual optical isomers, preferably by treatment with d- or l-tartaric acid.
• the resulting diastereoisomeric salt is recrystallized and reconverted to the free antipode.
• the reconversion is carried out by hydrolysis with, for example, a basic agent, such as an alkali metal hydroxide, e.g. sodium or potassium hydroxide, or ammonium hydroxide.
• a basic agent such as an alkali metal hydroxide, e.g. sodium or potassium hydroxide, or ammonium hydroxide.
• a more preferred embodiment involves the direct preparation of dextro- or levorotatory isomers of the compounds of formula I by the processes described under items (a) and (b), from their optically active starting materials.
• starting materials under item (b) can be resolved as described above for the final product.
• the piperidine starting materials are resolved essentially as described above with preferably d- or l-tartaric acid.
• the free antipodes thereof are condensed as indicated under item (a) to form the corresponding dextro- or levorotatory isomers of the compounds of formula I.
• treatment of a racemic pyridine-methanol compound under item (a) with l-tartaric acid in an alcoholic solution at preferably elevated temperatures will afford on cooling the crystalline l-diastereoisomeric salt.
• the salt is recrystallized and hydrolyzed in an aqueous solution with, for example, an alkaline hydroxide, e.g. sodium hydroxide.
• the free antipode is recrystallized to a constant rotation and is the dextrorotatory isomer. Condensation of this dextroratory isomer with the butyrophenone under item (a) affords the dextrorotatory compound of formula I.
• the d, l -piperidine is treated with d-tartaric acid, the l -piperidine is obtained, which, when reacted with the butyrophenone, results in the levorotatory form of the compounds of formula I, which are more useful as antihypertensive agents.
• the pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients suitable for either enteral or parenteral application.
• Preferred are tablets and gelatin capsules comprising the active ingredient together with (a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, (b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol, for tablets also (c) binders, e.g.
• Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously fatty emulsions or suspensions.
• compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
• adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
• Said pharmaceutical compositions may also contain other therapeutically valuable substances. They are prepared according to conventional mixing, granulating or coating methods respectively and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient.
• the mixture of 18 g of the above benzyl alcohol, 180 ml of glacial acetic acid, 20 ml of water and 9 g of 10% palladium on charcoal is treated with hydrogen at 60 p.s.i. and room temperature. Following the theoretical uptake of hydrogen, the reaction mixture is filtered to remove the catalyst. The filtrate is evaporated under reduced pressure and the residue treated with 50% aqueous sodium hydroxide. The resulting mixture is extracted with chloroform; the chloroform extract is dried and evaporated under reduced pressure to yield the ⁇ -methyl- ⁇ -(4-piperidyl)-benzyl alcohol, melting at 172°-175°.
• the mixture of 10 g thereof and 100 ml of tetrahydrofuran diethyl ether (3:1) is added dropwise to a solution of methylmagnesium iodide prepared from 5 g of magnesium and 28.4 g of methyl iodide and 40 ml of diethyl ether.
• the reaction mixture is refluxed for 4 hours and then decomposed with 36 ml of saturated aqueous ammonium chloride solution.
• the solvents are evaporated under reduced pressure and the inorganic salts remaining are dissolved in 5% aqueous hydrochloric acid.
• the acid solution is extracted with methylene chloride.
• the organic extract is then dried and evaporated to give the ⁇ -methyl- ⁇ -(N-acetyl-4-piperidyl)-p-chlorobenzyl alcohol.
• the mixture of 10 g thereof, 10 g of 10% palladium on charcoal, 225 ml of glacial acetic acid and 25 ml of water is treated with hydrogen at 4.8 atm. at room temperature. Following the theoretical uptake of hydrogen, the reaction mixture is filtered to remove the catalyst. The filtrate is evaporated under reduced pressure and the residue treated with 50% aqueoussodium hydroxide. The resulting base is crystallized and collected on the filter, washed with water and recrystallized from ethanol to yield the ⁇ -methyl- ⁇ -(4-piperidyl)-p-fluorobenzyl alcohol, melting at 184°-186°.
• the diethyl ether extract is then dried and evaporated under reduced pressure to yield yellow oil.
• This yellow oil is dissolved in ethanol and converted into a hydrochloride with ethanolic hydrogen chloride to give 4'-fluoro-4[4-( ⁇ -hydroxy- ⁇ -methylphene-ethyl)-piperidino]-butyrophenenone hydrochloride with a melting point of 170°-180° dec.
• the starting material is prepared as given below: To a mixture of 4.8 g of magnesium and 100 ml of diethyl ether is added dropwise a solution of 28.4g of methyl iodide in 200 ml of diethyl ether. The resulting mixture is refluxed for 30 minutes, followed by the addition of 20.0 g of 1-(4-pyridyl)-acetophenone [prepared according to method described in J. Amer. C.S., 70, 3997 (1968)] in 300 ml of tetrahydrofuran, added dropwise. The total reaction mixture is then refluxed for four hours, cooled and treated with 50 ml of saturated ammonium chloride, added dropwise.
• the reaction mixture is worked up inthe usual manner as described in the previous examples.
• the product is finally isolated as a foam and is the 4'-fluoro-4-[4-( ⁇ -hydroxy- ⁇ -methyl-p-chloro-m-trifluoromethylbenzyl)-piperidino]-butyrophenone.
• the starting material 4-( ⁇ -hydroxy- ⁇ -methyl- ⁇ -p-chloro-m-trifluoromethylbenzyl)-piperidine is prepared in the usual manner described in the other examples by reacting a Grignard reagent of p-chloro-m-trifluoromethyl phenyl magnesium bromide with 4-acetyl-pyridine and the resulting product which is ⁇ -methyl- ⁇ -(4-pyridyl)-p-chloro-m-trifluoromethylbenzyl alcohol reduced with hydrogen using platinum oxide as the catalyst to givethe starting material.
• the hydrochloride salt of the starting material is prepared in the usual manner and has a melting point of 128°-130°.
• the compound 4'-fluoro-4-[4-( ⁇ -hydroxy- ⁇ -methyl-m-trifluoromethylbenzyl)-piperidino]-butyrophenone is prepared according to Example 6 except that 3-bromo-benzotrifluoride is used to react with magnesium turnings to prepare the usual Grignard reagent.
• All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 25 ml of water and the suspension added to the boiling solution of the polyethylene glycol in 100 ml of water. The paste formed is added to the powders which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35°, broken on a screen with 1.2 mm openings and compressed into tablets using flat punches with 4.8 mm diameter, uppers bisected.

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• Chemical & Material Sciences (AREA)
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• Hydrogenated Pyridines (AREA)
• Plural Heterocyclic Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1973
  • 1973-10-18 US US05/407,737 patent/US3992546A/en not_active Expired - Lifetime

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